dbSNP rs121908813: TMEM127:c.-18C>T (chr2-96265399-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2PP5_ModerateBP4

The NM_017849.4(TMEM127):c.-18C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TMEM127
NM_017849.4 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 2.72

Publications

1 publications found

Variant links:

Genes affected

TMEM127 (HGNC:26038): (transmembrane protein 127) This gene encodes a transmembrane protein with four predicted transmembrane domains. The protein is associated with a subpopulation of vesicular organelles corresponding to early endosomal structures, with the Golgi, and with lysosomes, and may participate in protein trafficking between these structures. Mutations in this gene and several other genes cause pheochromocytomas. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Aug 2022]

TMEM127 Gene-Disease associations (from GenCC):

hereditary pheochromocytoma-paraganglioma
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
pheochromocytoma
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
renal cell carcinoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

TMEM127 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-96265399-G-A is Pathogenic according to our data. Variant chr2-96265399-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 126961.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM127	NM_017849.4 link	c.-18C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 4	ENST00000258439.8	NP_060319.1	O75204
TMEM127	NM_017849.4 link	c.-18C>T		5_prime_UTR_variant	Exon 2 of 4	ENST00000258439.8	NP_060319.1	O75204

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8 link	c.-18C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 4	1	NM_017849.4	ENSP00000258439.3		O75204
TMEM127	ENST00000258439.8 link	c.-18C>T		5_prime_UTR_variant	Exon 2 of 4	1	NM_017849.4	ENSP00000258439.3		O75204

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1208598

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

588032

African (AFR)

AF:

0.00

AC:

AN:

23908

American (AMR)

AF:

0.00

AC:

AN:

12922

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17102

East Asian (EAS)

AF:

0.00

AC:

AN:

27412

South Asian (SAS)

AF:

0.00

AC:

AN:

50834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28654

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3422

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

994768

Other (OTH)

AF:

0.00

AC:

AN:

49576

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Pheochromocytoma

Pathogenic:1

Familial Cancer Clinic, Veneto Institute of Oncology

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Hereditary pheochromocytoma-paraganglioma

Pathogenic:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=35/265

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over